Fatty acid metabolism in the hypothalamic parenchyma of mice: a novel role for medium-chain fatty acids? (#156)

Obesity is associated with lipid accumulation in non-adipose tissues, which
can result in “lipotoxic” outcomes such as impaired insulin action and
apoptosis. We have recently shown that “lipotoxicity” extends to the central nervous
system (CNS), such that obesity induced by high-fat feeding results in lipid
deposition in the hypothalamus of mice1. Lipid deposition in the brain is postulated to affect energy homeostasis
and peripheral insulin action. Recent studies have challenged the dogma that
the CNS does not oxidise fatty acids2. Interestingly, diets that contain medium-chain fatty acids (MCFA) enhance fatty acid (FA) oxidation, increase energy expenditure and
improve insulin action when compared with diets containing long-chain fatty
acids (LCFA)3. Hence, the aim of this research was to compare the metabolic fates of MCFA and LCFA
in the hypothalamus.

FA metabolism was assessed using radiometric methods in hypothalamic-derived
immortalised and primary murine neurons, hypothalamic sections ex vivo and in mice in vivo. Neurons are capable of transporting FA across the plasma
membrane, oxidizing FA and storing FA as triglycerides. The oxidation to
storage ratio was 1:5 for LCFA and 4:1 for MCFA. Whole hypothalamus isolated from lean mice exhibit a
preference for LCFA oxidation rather than storage (10:1 ratio). FA administered directly into
the cerebrospinal fluid via the lateral ventricle were both oxidised and stored
as glycerides (1:4 and 25:1 oxidation:storage ratio for LCFA and MCFA,
respectively). When LCFA were administered via the carotid artery or via oral gavage, CNS FA
uptake and storage were low. Conversely, MCFA were readily able to cross from
the gut to the CNS via the circulation and were oxidised and stored at a 20:1
ratio. Thus, the parenchyma of the hypothalamus (including neurons) is capable
of FA transport, oxidation and storage, and MCFA may have a greater influence
on CNS FA metabolism than LCFA.